Implantable photonic devices for improved medical treatments · Implantable photonic devices for...

Implantable photonic devices forimproved medical treatments

Victor SheinmanArkady RudnitskyRakhmanbek ToichuevAbdyrakhman EshievSvetlana AbdullaevaTalantbek EgemkulovZeev Zalevsky

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Implantable photonic devices for improvedmedical treatments

Victor Sheinman,a Arkady Rudnitsky,a Rakhmanbek Toichuev,b Abdyrakhman Eshiev,c Svetlana Abdullaeva,cTalantbek Egemkulov,c and Zeev Zalevskya,*aBar-Ilan University, Faculty of Engineering, Ramat-Gan 5290002, IsraelbInstitute of Medical Problems, Southern Branch of National Academy of Sciences of the Kyrgyz Republic, 723506 Osh, Kyrgyz RepubliccRegional Clinical Hospital of Osh, 723504 Osh, Kyrgyz Republic

Abstract. An evolving area of biomedical research is related to the creation of implantable units that providevarious possibilities for imaging, measurement, and the monitoring of a wide range of diseases and intrabodyphototherapy. The units can be autonomic or built-in in some kind of clinically applicable implants. Because ofspecific working conditions in the live body, such implants must have a number of features requiring furtherdevelopment. This topic can cause wide interest among developers of optical, mechanical, and electronicsolutions in biomedicine. We introduce preliminary clinical trials obtained with an implantable pill and devicesthat we have developed. The pill and devices are capable of applying in-body phototherapy, low-level lasertherapy, blue light (450 nm) for sterilization, and controlled injection of chemicals. The pill is also capable ofcommunicating with an external control box, including the transmission of images from inside the patient’sbody. In this work, our pill was utilized for illumination of the sinus-carotid zone in dog and red light influenceon arterial pressure and heart rate was demonstrated. Intrabody liver tissue laser ablation and nanoparticle-assisted laser ablation was investigated. Sterilization effect of intrabody blue light illumination was applied duringa maxillofacial phlegmon treatment. © 2014 Society of Photo-Optical Instrumentation Engineers (SPIE) [DOI: 10.1117/1.JBO.19.10

.108001]

Keywords: biomedical optics; biophotonics; endoscopy; phototherapy.

Paper 140386R received Jun. 20, 2014; revised manuscript received Aug. 22, 2014; accepted for publication Sep. 5, 2014; publishedonline Oct. 3, 2014.

1 IntroductionPhotodynamic therapy (PDT) has been used in the last threedecades as a clinical technique for the treatment of several dis-eases, including cancer, rheumatoid arthritis, age-related macu-lar degeneration, skin disease, and arteriosclerosis.1–11 Oneimportant application of PDT is its application for antibacterialtreatments involving the killing of bacteria by reactive oxygenspecies generated in the presence of a photosensitizer andlight.12–14 Examples include inactivation of the bacteria in skinand wound infections and reduction in the density of nosocomialmultiresistant infections.15–18 The major advantage of antibac-terial PDT is that acquiring resistance is not simple and thecurrent resistance mechanisms exerted by bacteria against thecommon commercially available antibiotics do not protectagainst the mode of action of PDT.19

As with PDT, usage of light to biostimulate cells is acommon approach in low-level laser therapy (LLLT).20–24

We introduce a newly developed implantable pill that aims toperform in-body phototherapy, LLLT, blue light for sterilization,controlled injection of chemicals, and communication with anexternal control box including the transmission of images frominside the patient’s body. We present the pill as well as itspreliminary experimental validation.

The term PDT from a medical point of view can mean a largenumber of diverse effects on various organs and tissues of a liv-ing organism. In this paper, we conducted experiments havingpractical importance in the treatment of epilepsy (illumination of

sinus—carotid region), cancer of internal organs (laser ablationof liver tissues), and phlegmon (blue light therapy).

Note that the usage of a wireless capsule25,26 for endoscopyas a diagnostic device and for multipurpose robotic systems hasbeen demonstrated before in Ref. 27, while, in general, swallow-able-capsule technology28 is very useful for gastrointestinalendoscopy.29

In Sec. 2, we present the developed implantable pill. InSec. 3, we show the preliminary experimental results. This paperis concluded in Sec. 4.

2 Implantable PillOur proposal is to use photostimulation and phototherapyfrom inside the body. An important difference of this approachis that laser radiation can be delivered to specific internalorgan or tissue in vivo, without any loss of its coherence andpolarization.30,31 This fact is very significant for the imagingand shaping of beams for more efficient illumination. We willdo this with an implantable pill. Currently, all those medical pro-cedures are done externally. Thus, we have developed a specialpill that can be implanted into the body during medical surgeryand can then monitor the region of the wound by a cameralocated inside it as well as apply PDT or LLLT using its lightsources. Four light emitting diodes (LEDs) as sources wereinserted into the pill: at blue (450 nm) for sterilization and atgreen (518 nm), at red (650 nm), and at infrared (IR) (850 nm)for PDT. Images of the two different types of pills that werefabricated may be seen in Fig. 1. A control card is connected

*Address all correspondence to: Zeev Zalevsky, E-mail: [email protected] 0091-3286/2014/$25.00 © 2014 SPIE

Journal of Biomedical Optics 108001-1 October 2014 • Vol. 19(10)

Journal of Biomedical Optics 19(10), 108001 (October 2014)


http://dx.doi.org/10.1117/1.JBO.19.10.108001






mailto:[email protected]



to the pill and communication is done through Bluetooth with anexternal computer. The camera sends its images at a frequencyof 2.4 GHz to an external receiver/transmitter unit which is alsoconnected to a computer.

Note that the reason we used cables in the current paper anddid not use wireless as in Ref. 26 is because our implantablemodule is now more complicated than that in Ref. 26. Our

current pill includes several units. The implantation of the con-trol unit and power sources is expected to be subcutaneous forminimization of surgical intervention, but the camera and lightsources units are supposed to be adjusted to the necessary organof the body.

Our clinical trials performed with the implantable pill wereperformed both in rabbits as well as in dogs. In Fig. 2, we

2 cm

Batteries of the camera

Battery of the control card

Control card

The pill

2 cm

Fig. 1 Two types of the fabricated pills. The pill in the left figure contains a camera and four light emittingdiodes at blue for sterilization, at green, at red, and at IR. The camera and the light sources are controlledthrough the control card via Bluetooth. The camera sends its images to an external transmitter/receiver ata frequency of 2.4 GHz. The pill in the right figure contains same parts excluding the camera and ispackaged to one piece.

Fig. 2 The implantation experiments. (a) Wireless implant. (b)–(h) Implantation in rabbits: (b) electricalenergy connection by a hypodermic port. (c) Injection of the hypodermic port as part of the implantationprocess. Electrical hypodermic port is applied. (d) and (e) Injection of lidocaine through the hypodermicport, electrical hypodermic port is used. Light in the rabbit is turned on. (f) Repeated dissection of a woundafter 14 days of experiment. Illumination is on, infusion catheter is present. (g) Pulsoximeter applied onrabbit’s ear. (h) Implanted light in rabbit. Energy is supplied through the hypodermic port. (i) Implantationexperiments in dogs.


Sheinman et al.: Implantable photonic devices for improved medical treatments


present the implantation experiments. In Fig. 2(a), we show ourwireless implant. We performed sterilization before implanta-tion with 70% ethanol for 15 min. Figures 2(b)–2(h) are relatedto implantation in rabbits. In Fig. 2(b), we show the electricalenergy connection by hypodermic port. In Fig. 2(c), one may seethe injection of the electrical hypodermic port as part of theimplantation process. In Figs. 2(d) and 2(e), one may see theinjection of lidocaine through the hypodermic port. The electri-cal hypodermic port is used. The light in the rabbit is turned on.In Fig. 2(f), we repeat the dissection of a wound after 14 days ofexperiment. The illumination is on and an infusion catheter ispresent. In Fig. 2(g), one may see a pulsoximeter applied on

the rabbit’s ear. In Fig. 2(h), one may see the implanted lightturned on inside the rabbit. The energy is supplied throughthe hypodermic port. In Fig. 2(i), we show our implantationexperiment performed in dogs.

3 Experimental ResultsIn Figs. 3(a) and 3(b), we present preliminary clinical experien-tial results where the given developed pill was implanted into adog close to sinus carotid zone and used to demonstrate that aninternal illumination of 650 nm, having a 2700 mcd luminousintensity can control the arterial pressure and the heart beat rate.

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Fig. 3 (a) and (b) Experimental demonstration showing that through photostimulation of the “sinuscarotid zone” one may cause reduction in arterial pressure and an increase in the heart rate (can begood for heart diseases where one needs to control the blood pressure and the heart rate). The redarrow designated the timing when the illumination was stopped.

Fig. 4 Illumination from inside the body (900-nm wavelength, power 3 W focused to diameter 50 μm) ofliver with implanted gold nanoparticles (NPs) having absorption resonance at the illumination wave-length. After histology analysis we saw that in the ablated liver with the NP, the hemorrhage is observedto be 1.5 to 2 times denser in comparison with the reference case (laser illuminated liver without NP).(a) The experiment. (b) Microscope image for laser illumination without NP. (c) Microscope image forlaser illumination with NP.




This may be also very applicable for controlling blood pressureand heart rate parameters in humans. In Fig. 3, arterial pressureversus time is presented. One can see that in the case ofillumination of the sinus carotid region, systolic and diastolicpressures are larger, in comparison with the case when illumi-nation was stopped. The red arrow in Figs. 3(a) and 3(b) des-ignates the timing when the illumination was stopped. One maysee how the blood pressure is reduced and the heart rate indi-cator is increased right after the illumination is stopped. Thus,in-body illumination may increase the healing rate of a wound.

Figure 4 presents another application for the in-bodyimplantable pill. Here, we injected nanoparticles (NPs) into aliver and applied phototherapy from inside the body. The illu-minated gold NPs had surface plasmon resonance at the illumi-nation wavelength (900 nm). Counting the overall hemorrhagefields’ area was done by sectioning and counting the “hemor-rhaged” squares using an Olympus microscope (OlympusCorporation, Shinjuku, Tokyo, Japan). After histology analysisof the liver, we saw that in the ablated liver with theNP, the hemorrhage is observed to be 1.5 to 2 times denser incomparison with the reference case (laser illuminated liverwithout NP).

The next set of experiments was performed on rabbits. InTable 1, we present the experimentally extracted results for theoxymetry and the heart rate when the implantable pill was illu-minating the sinus carotid. In this experiment, illumination wasapplied during 8 days (20 min daily), and the organism reactionon illumination was estimated by heart rate and oximetry.Measurements were carried out directly before and after illumi-nations. The goal of this experiment was to see the change of theinfluence of same illumination on organism during the postsur-gery period.

For illustration purposes, the obtained results as presented inTable 1, are plotted as curves in Figs. 5(a) and 5(b), respectively.

Three days after implantation, the illumination of sinuscarotid resulted in the reduction of the heart rate and in anincrease of oxygen saturation in blood. The difference of heartrate reached 20% and the difference in oxygen saturation was10%. This fact can be explained as a positive influence of lighton postoperative stress. From days 4 to 8, we have observed theopposite reaction, with both differences reaching the value of10%. This fact can be explained as the reaction of a nonstressedorganism.

Our next experiment included the investigation of the liverhealing after heat ablation. Illumination was applied for 20 minin a daily manner. After the experiment was finished, histologyprobes were taken. The histology results are described inTable 2. The typical way for estimation of the liver tissue regen-eration level is to count the multinuclear cells (hepatocyteshaving more than one nucleus). Quantities of three types of

Table 1 (a) Oxymetry data for illumination on sinus carotid. (b) Heartrate data for illumination on sinus carotid.

# ofexperiment

# of rabbit

Average STD1 2 5

Oxymetry data

1 Day of experiment 1 1 1

Before illumination 99 90 86 88.66 2.3

After illumination 96 87 86 89.6 5.5

2 Day of experiment 3 2

Before illumination 84 79 81.5 3.5

After illumination 95 86 90.5 6.4







Heart rate data

1 Day of experiment 1 1 1

Before illumination 214 210 171 198.3 23.7

After illumination 233 148 178 186.3 43.1










Fig. 5 Experimental results. (a) Average oxygen saturation. (b) Average heart rate.




cells were counted: one nuclear cell, two nuclear cells, anddegenerative hepatocites cells. All were counted for healthyliver (norm), for preablated liver without illumination (ref.),and for preablated liver with illumination (exp). The notationof “þ∕−” designates the standard deviation, i.e., the error ofthe performed measurements.

Colored hematoxylin-eosin images taken at a magnificationof 400× under the microscope can be seen in Fig. 6 for reference[Fig. 6(a)] and for illuminated cells [Fig. 6(b)].

Histological studies of the material obtained from four rab-bits with burn defects in the liver showed the following results:In the control experiments, in which a surface burn of the liveralone was performed; in 1-week observation hepatocytes whichshowed necrotic and necrobiotic changes, insular necrosisof hepatocytes, marked edema, hyperemia, and sites of hemor-rhages. In comparison with normal tissue, the quantities ofone and two nuclear hepatocytes and degenerative cells wereincreased (see Table 2).

After a daily contact application of red light radiation(20 min a day), marked edema, hyperemia, decondensation ofliver tissue were observed; necrotic and necrobiotic changeswere less expressed. In comparison with control experiments,the quantity of one nuclear hepatocytes cells was increased,while the quantities of two nuclear hepatocytes and degenerativecells were not changed.

In another experiment with a 2-week observation period, inreference experiments we observed islets of infiltration of netro-philes, lymphocytes, hyperemia of small veins, hepatocytesnecrosis sites, decondensation of liver tissue, and marked hem-orrhage. The quantity of degenerative cells was decreased andthe quantity of nuclear hepatocytes cells was not changed.

In basic experiments, the same picture was observed; how-ever, tissue was less decondensated and the structure of hepa-tocytes was more preserved, while infiltration of lymphocyteswas more pronounced in portal tracts. The quantity of twonuclear cells in the illuminated region was larger than at thenonilluminated region. The quantity of degenerative cells wasdecreased.

The summary of the abovementioned results are shown inFig. 7, where Fig. 7(a) is the chart for the quantity of the degen-erative cells, and Figs. 7(b) and 7(c) show the quantities of oneand two nuclear hepatocytes cells, respectively.

Thus, as a summary of this experimental section, basicexperiments showed an improvement of the regenerative capac-ity of liver tissue during 2 weeks of illumination as compared toreference experiments. The compensatory reaction of hepato-cytes to trauma is accompanied by an increase in the quantityof one and two nuclear hepatocytes cells in both the referencesas well as the experimental samples. With illumination, thequantity of degenerative cells was decreased after a period of2 weeks.

Our last experiment offers a new approach to deal with amedical condition known as phlegmon of the maxillofacialarea. To date, a common treatment for such an infection can takeup to 2 weeks and it includes surgery in which the infected areais removed followed by antibiotic care.32,33 The recovery proc-ess after such a procedure can take a few weeks during which theinfection can spread to the brain. We have decided to investigatethe effect that light therapy has on the recovery process aftersuch a treatment. In order to do so, we conducted a clinicalexperiment which included 26 patients that were diagnosedas suffering from phlegmon of the maxillofacial area. All

Table 2 Histology results for liver regeneration.

1 week 2 week

Norm “þ∕−” Ref. “þ∕−” Exp. “þ∕−” Ref. “þ∕−” Exp. “þ∕−”

1- nuclear 67.714 16.500 82.357 29.000 96.857 12.000 91.200 20.000 94.714 15.000

2- nuclear 20.857 10.500 24.928 11.250 24.285 7.500 24.000 6.000 30.800 9.500

Degener. 3.500 3.000 23.071 10.750 22.857 5.750 14.250 2.000 8.800 2.000

Fig. 6 (a). Reference photo obtained after 2 weeks. Colored: hematoxylin-eosin. Microscope magnifi-cation of 400×. (b). Experimental results photo obtained after 2 weeks. Colored: hematoxylin-eosin.Microscope magnification 400×.




patients underwent a surgery to remove the infected area. A con-trol group of 15 patients received antibiotic treatments while agroup of 11 patients received both antibiotic treatments andthree sessions of light irradiation therapy in which an implant-able device based on our technology was installed inside theirhead area. One of the patients participating in our experimentaltrials is presented in Fig. 8. For this experiment, only blue lightat 450 nm was used. Each session included irradiation of 20 minwith a 450 nm, 1 candela luminous intensity LED (KingbrightAA3535QB24Z1S, New Taipei City, Taiwan) that was insertedwith a catheter.

Thus for the experiment of Fig. 8, we dismantled our pill andused only portions of it. The reason for illumination using onlyblue light LEDs without our pill is due to the medical compat-ibility of materials that our pill contains. As of now, we haveonly biocompatibility (for experiments on animals), but not fullmedical compatibility. The interval between irradiations was 3days. The reason for choosing a wavelength of 450 nm is thatwhile it is considered safe to humans, it has been shown that

irradiating bacteria with similar wavelengths has a negativeeffect on their ability to prosper.34

The first irradiation session was carried out right after thesurgery and after each session samples were taken for testingthe leukocyte levels and number of bacterial colonies.

The results of this experiment are shown in Fig. 9. As can beseen, the number of bacterial colonies decreased faster amongthe group of patients that received irradiation therapy as com-pared with the control group. Hence, it can be assumed thatcombining light therapy with antibiotic treatment shortens therecovery process. Note that the chart in Fig. 9 is logarithmicand the decrease in the bacteriology measurement in the caseof irradiation was >2 orders of magnitude.

In addition, leukocyte levels decreased more slowly amongpatients that received irradiation therapy as compared withthe control group (see Fig. 10). This result can be explained bythe fact that light irradiation therapy has a positive effect on

Fig. 7 (a). Degenerative cells’ quantity. (b). One nuclear hepatocites cells’ quantity. (c). Two nuclearhepatocites cells’ quantity.

Fig. 8 Patient with experimental setup adjusted. Fig. 9 Bacteriology measurement results.




the immune system. It has been shown that visible lightirradiation (400 to 700 nm) led to a significant increase in thenumber of lymphocytes.35

In light of these findings, one may conclude that the irradi-ation therapy led to a more effective response of the immunesystem which manifested itself in the continuous formationof leukocytes.

These preliminary results demonstrate the positive effect thatlight irradiation therapy has when combining it with antibioticcare as part of a novel medical treatment for phlegmon of themaxillofacial area.

4 ConclusionsWe have introduced an implantable pill that has several function-alities, including having light sources at different wavelengthscapable of performing phototherapy treatments. In addition tolow laser light treatment, it includes UV light for sterilizationand has the capability for controlled injection of chemicals aswell as the capability of transmission of images from insidethe patient’s body to an external box viawireless communication.

We presented several preliminary clinical results performedwith dogs, rabbits, and humans, and showed the biomedicalpotential of the proposed implantable pill. In this experiment,we showed how illuminating the wound from inside assists inits healing, how illumination can control the blood pressure, theaverage oxygen saturation, and the heart rate. Specific experi-ments with rabbit’s liver cells were performed.

We presented preliminary clinical results demonstrating thepositive effect that light irradiation therapy has when combiningit with antibiotic care as part of a medical treatment for phleg-mon of the maxillofacial area.

We also showed how the illumination related treatment canbe accompanied with NPs for further affecting a given tissue.

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Victor Sheinman received his MD degree in the field of stomatologyin 1963, PhD degree in the field of maxillofacial medicine in 1970,and a higher doctoral degree (Doctor of Sciences) in the field ofmaxillofacial medicine in 1989. He was the chief of the AcademicDepartment of Maxillofacial Medicine. He is an author of more than100 publications, two monographs, one surgeon atlas, and 20 pat-ents. Now, he is a scientific researcher at Bar-Ilan University.

Arkady Rudnitsky received his MSc degree in the field of systemengineering at Samara State Aerospace University in 1995 and, inaddition, a PhD degree in the field of electro-optics at Tel-AvivUniversity in 2012. He is currently the electro-optics lab engineerin the Engineering Department of Bar-Ilan University. His researchinterests are all-optical computational devices, novel application ofnano-mechanical devices in optics and biomedical optics andengineering.

Rakhmanbek Toichuev received his MD degree in the field of sto-matology in 1970. He worked in a regional children’s hospital from1972 to 1995. In 1989, he received a PhD degree in the field of pedi-atric surgery. Since 1994, he has been the director of the Institute of

Medical Problems of the Academy of Science of Kyrgyzstan. He hasmore than 250 publications and about 20 patents.

Abdyrakhman Eshiev received his MD degree in the field of stoma-tology in 1984, PhD degree in the maxillofacial medicine at 2004, anda higher doctoral degree (Doctor of Sciences) at 2011. Now, he is aprofessor at the Medical Department of Osh State University. He hasmore than 100 publications and about 30 patents.

Svetlana Abdullaeva received her MD degree in the field of stoma-tology. She is a resident physician in the Maxillofacial Department ofthe Regional Hospital of Osh, Kyrgistan. In addition, she is involved inscientific research for a PhD degree in the topic of using blue light inthe treatment of abscesses of the maxillofacial region.

Talantbek Egemkulov received his MD degree in the field of stoma-tology in 2010. He is a resident physician in the MaxillofacialDepartment of the Regional Hospital of Osh, Kyrgistan. In addition,he is involved in scientific research for a PhD degree. He has 6publications.

Zeev Zalevsky received his BSc and direct PhD degrees in electricalengineering from Tel-Aviv University in 1993 and 1996, respectively.He is currently a full professor in the Faculty of Engineering in Bar-IlanUniversity, Israel. His major fields of research are optical super-res-olution, biomedical optics, nanophotonics, and electro-optical devi-ces. He published more than 350 journal papers, 190 conferenceproceeding papers, 315 international presentations, 32 issued pat-ents, 9 authored and edited books, and 27 book chapters.




http://dx.doi.org/10.1100/2012/137805

http://dx.doi.org/10.1111/nyas.2000.917.issue-1

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